Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

BCR-ABL1-negative myeloproliferative neoplasms are classically represented by primary myelofibrosis, polycythemia vera, and essential thrombocythemia. These entities are stem cell-derived clonal disorders characterized by hematopoietic progenitor autonomy or hypersensitivity to cytokines, most of them presenting mutations in Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL). Deregulation of pro- and antiapoptotic genes is also claimed as an important mechanism involved in cell resistance to cell death and accumulation of myeloid cells in myeloproliferative neoplasms. Apoptosis, as one of the best-characterized types of programmed cell death, has a clear role in hematopoiesis control. However, the exact pathways affected in BCR-ABL1-negative myeloproliferative neoplasms have not yet been fully clarified. This chapter will explore the modifications affecting programmed cell death pathways involved in myeloid proliferation and how these alterations might be exploited in single or combined targeted therapeutic strategies

Collagen Family and Other Matrix Remodeling Proteins Identified by Bioinformatics Analysis as Hub Genes Involved in Gastric Cancer Progression and Prognosis

Gastric cancer has remained in the top five cancers for over ten years, both in terms of incidence and mortality due to the shortage of biomarkers for disease follow-up and effective therapies. Aiming to fill this gap, we performed a bioinformatics assessment on our data and two additional GEO microarray profiles, followed by a deep analysis of the 40 differentially expressed genes identified. PPI network analysis and MCODE plug-in pointed out nine upregulated hub genes coding for proteins from the collagen family (COL12A1, COL5A2, and COL10A1) or involved in the assembly (BGN) or degradation of collagens (CTHRC1), and also associated with cell adhesion (THBS2 and SPP1) and extracellular matrix degradation (FAP, SULF1). Those genes were highly upregulated at the mRNA and protein level, the increase being correlated with pathological T stages. The high expression of BGN (p = 8 × 10−12), THBS2 (p = 1.2 × 10−6), CTHRC1 (p = 1.1 × 10−4), SULF1 (p = 3.8 × 10−4), COL5A1 (p = 1.3 × 10−4), COL10A1 (p = 5.7 × 10−4), COL12A1 (p = 2 × 10−3) correlated with poor overall survival and an immune infiltrate based especially on immunosuppressive M2 macrophages (p-value range 4.82 × 10−7–1.63 × 10−13). Our results emphasize that these genes could be candidate biomarkers for GC progression and prognosis and new therapeutic targets

Smooth Migration of CERN Post Mortem Service to a Horizontally Scalable Service

The Post Mortem service for CERNs accelerator complex stores and analyses transient data recordings of various equipment systems following certain events, like a beam dump or magnet quenches. The main purpose of this framework is to provide fast and reliable diagnostic to the equipment experts and operation crews to decide whether accelerator operation can continue safely or whether an intervention is required. While the Post Mortem System was initially designed to serve CERNs Large Hadron Collider (LHC), the scope has been rapidly extended to include as well External Post Operational Checks and Injection Quality Checks in the LHC and its injector complex. These new use cases impose more stringent time-constraints on the storage and analysis of data, calling to migrate the system towards better scalability in terms of storage capacity as well as I/O throughput. This paper presents an overview on the current service, the ongoing investigations and plans towards a scalable data storage solution and API, as well as the proposed strategy to ensure an entirely smooth transition for the current Post Mortem users

First Operational Experience of DSL Based Analysis Modules for LHC Hardware Commissioning

The Large Hadron Collider powering systems have been tested and commissioned before to start the second run of physics production. This commissioning used for the first time analysis modules defined directly by system experts in an english-like domain specific language. In these modules, the experts defined assertions that the data generated by the powering tests must verify in order for the test to pass. These modules concerned 4 tests executed for more than 1000 systems. They allowed experts to identify issues that were hidden behind the repetitive manual analysis performed during the previous campaigns. This paper describes this first operational experience of the analysis modules, as well as the replay of all the previous campaign with them. It will also present a critical point of view on these modules to identify their drawbacks and the next step to improve this system

Towards a Second Generation Data Analysis Framework for LHC Transient Data Recording

During the last two years, CERNs Large Hadron Collider (LHC) and most of its equipment systems were upgraded to collide particles at an energy level twice higher compared to the first operational period between 2010 and 2013. System upgrades and the increased machine energy represent new challenges for the analysis of transient data recordings, which have to be both dependable and fast. With the LHC having operated for many years already, statistical and trend analysis across the collected data sets is a growing requirement, highlighting several constraints and limitations imposed by the current software and data storage ecosystem. Based on several analysis use-cases, this paper highlights the most important aspects and ideas towards an improved, second generation data analysis framework to serve a large variety of equipment experts and operation crews in their daily work

Molecular Aspects of Hypoxic Stress Effects in Chronic Ethanol Exposure of Neuronal Cells

Experimental models of a clinical, pathophysiological context are used to understand molecular mechanisms and develop novel therapies. Previous studies revealed better outcomes for spinal cord injury chronic ethanol-consuming patients. This study evaluated cellular and molecular changes in a model mimicking spinal cord injury (hypoxic stress induced by treatment with deferoxamine or cobalt chloride) in chronic ethanol-consuming patients (ethanol-exposed neural cultures (SK-N-SH)) in order to explain the clinical paradigm of better outcomes for spinal cord injury chronic ethanol-consuming patients. The results show that long-term ethanol exposure has a cytotoxic effect, inducing apoptosis. At 24 h after the induction of hypoxic stress (by deferoxamine or cobalt chloride treatments), reduced ROS in long-term ethanol-exposed SK-N-SH cells was observed, which might be due to an adaptation to stressful conditions. In addition, the HIF-1α protein level was increased after hypoxic treatment of long-term ethanol-exposed cells, inducing fluctuations in its target metabolic enzymes proportionally with treatment intensity. The wound healing assay demonstrated that the cells recovered after stress conditions, showing that the ethanol-exposed cells that passed the acute step had the same proliferation profile as the cells unexposed to ethanol. Deferoxamine-treated cells displayed higher proliferative activity than the control cells in the proliferation–migration assay, emphasizing the neuroprotective effect. Cells have overcome the critical point of the alcohol-induced traumatic impact and adapted to ethanol (a chronic phenomenon), sustaining the regeneration process. However, further experiments are needed to ensure recovery efficiency is more effective in chronic ethanol exposure

Kinetics and persistence of cellular and humoral immune responses to SARS-CoV-2 vaccine in healthcare workers with or without prior COVID-19

SARS-CoV-2 vaccines are highly efficient against severe forms of the disease, hospitalization and death. Nevertheless, insufficient protection against several circulating viral variants might suggest waning immunity and the need for an additional vaccine dose. We conducted a longitudinal study on the kinetics and persistence of immune responses in healthcare workers vaccinated with two doses of BNT162b2 mRNA vaccine with or without prior SARS-CoV-2 infection. No new infections were diagnosed during follow-up. At 6 months, post-vaccination or post-infection, despite a downward trend in the level of anti-S IgG antibodies, the neutralizing activity does not decrease significantly, remaining higher than 75% (85.14% for subjects with natural infection, 88.82% for vaccinated after prior infection and 78.37% for vaccinated only). In a live-virus neutralization assay, the highest neutralization titres were present at baseline and at 6 months follow-up in persons vaccinated after prior infection. Anti-S IgA levels showed a significant descending trend in vaccinated subjects (p < 0.05) after 14 weeks. Cellular immune responses are present even in vaccinated participants with declining antibody levels (index ratio 1.1-3) or low neutralizing activity (30%-40%) at 6 months, although with lower T-cell stimulation index (p = 0.046) and IFN-γ secretion (p = 0.0007) compared to those with preserved humoral responses.1293130513EU Horizon 202

Mesoporous Silica Materials Loaded with Gallic Acid with Antimicrobial Potential

This paper aimed to develop two types of support materials with a mesoporous structure of mobile crystalline matter (known in the literature as MCM, namely MCM-41 and MCM-48) and to load them with gallic acid. Soft templating methodology was chosen for the preparation of the mesoporous structures&mdash;the cylindrical micelles with certain structural characteristics being formed due to the hydrophilic and hydrophobic intermolecular forces which occur between the molecules of the surfactants (cetyltrimethylammonium bromide&mdash;CTAB) when a minimal micellar ionic concentration is reached. These mesoporous supports were loaded with gallic acid using three different types of MCM&mdash;gallic acid ratios (1:0.41; 1:0.82 and 1:1.21)&mdash;and their characterizations by FTIR, SEM, XRD, BET and drug release were performed. It is worth mentioning that the loading was carried out using a vacuum-assisted methodology: the mesoporous materials are firstly kept under vacuum at ~0.1 barr for 30 min followed by the addition of the polyphenol solutions. The concentration of the solutions was adapted such that the final volume covered the wet mesoporous support and&mdash;in this case&mdash;upon reaching normal atmospheric pressure, the solution was pushed inside the pores, and thus the polyphenols were mainly loaded inside the pores. Based on the SBET data, it can be seen that the specific surface area decreased considerably with the increasing ratio of gallic acid; the specific surface area decreased 3.07 and 4.25 times for MCM-41 and MCM-48, respectively. The sample with the highest polyphenol content was further evaluated from a biological point of view, alone or in association with amoxicillin administration. As expected, the MCM-41 and MCM-48 were not protective against infections&mdash;but, due to the loading of the gallic acid, a potentiated inhibition was recorded for the tested gram-negative bacterial strains. Moreover, it is important to mention that these systems can be efficient solutions for the recovery of the gut microbiota after exposure to antibiotics, for instance